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1.
The potency of several platelet-activating factor (PAF) receptor antagonists was measured by observing their inhibitory effects
against PAF induced platelet aggregation. Their selectivity was assessed by monitoring their effect on platelet aggregation
induced by arachidonic acid (AA) and adenosine diphosphate (ADP). The antagonists inhibited platelet aggregation induced at
the PAF EC50 (0.023 μM) with the following rank order of potency: WEB 2086> WEB 2170> SRI 64–412> SRI 63–675> BN 52021>kadsurenone> SRI
63–441> alprazolam. While the antagonists had no inhibitory effect at the EC50 for ADP (10 μM), they did inhibit platelet aggregation induced at the EC50 for AA (55 μM). However, there was considerable variability in the slope of the inhibitory response and the relative potency
of each antagonist against PAF induced platelet aggregation as compared to AA induced platelet aggregation. The antagonist
IC50 (μM) against PAF and AA were as follows, with those that showed significantly different (p<0.01) slopes indicated by an asterisk:
SRI 63-441* (3.8, 15.1); SRI 63-675 (1.4, 36.2); SRI 64-412 (0.5, 10.5); BN 52021* (2.4, 58.9); kadsurenone* (2.8, 28.3); alprazolam* (10, 25); WEB 2086 (0.055, 0.220), and WEB 2170 (0.107, 0.534). Therefore, in rabbit whole blood the antagonists were potent,
although not completely selective, inhibitors of PAF induced platelet aggregation. These results suggest that the mode of
action of PAF and AA induced platelet aggregation may share some common features. However, since the slope of the inhibitory
response against PAF and AA for some antagonists differed, mechanistic differences in their action appear to exist.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
2.
[3H]Platelet-activating factor (PAF) binding to rabbit platelet membranes was examined before and after 20 min preincubation
at 25°C in the presence of PAF, lysoPAF, or of five different PAF receptor antagonists (L 652731, BN 52021, WEB 2086, BN 52111
and BN 52115). When platelet membranes were not washed after preincubation with PAF or PAF antagonists, no significant specific
binding of [3H]PAF was observed, which suggests full occupancy of the binding sites. When membranes were extensively washed, full recovery
of specific [3H]PAF binding was attained with L 652731 and partial recoveries (60%, 55% and 30%) were reached with BN52021, WEB 2086 and
PAF, respectively; no recovery was seen with the dioxolanes BN 52111 and BN 52115. Scatchard analysis of the binding data
indicated that no significant change in the dissociation constant (Kd) and maximum number of binding sites (Bmax) occurred after preincubation of platelet membrane with L 652731, whereas a reduction of Bmax was observed when PAF and BN 52021 were measured. When platelet membranes were preincubated with WEB 2086, Bmax and Kd significantly increased. The data suggest differing binding properties for PAF and the PAF antagonists. Some of the PAF antagonists
may tightly bind to the PAF receptor site(s) and/or irreversibly modify or downregulate PAF recognition sites. Our results
also suggest that the interaction of PAF receptor antagonists with PAF receptor can be divided into at least two components,
namely a reversible component and an irreversible one.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
3.
Platelet-activating factor (PAF) activates human platelets by binding to a putative PAF receptor which evokes the rapid formation
of inositol-1,4,5-trisphosphate (IP3) by phospholipase C mediated phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis. Stimulation of [3H]inositol-labeled human platelets by PAF (1 nM-1μM) resulted in a concentration-dependent increase of intracellular IP3, IP2 and inositolmonophosphate (IP1). IP1 levels increased up to three-fold upon maximum stimulation by 100 nM PAF. The EC50 concentration for PAF was 1.2±0.3 nM. Addition of the hetrazepinoic PAF antagonist, WEB 2086, inhibited PAF stimulated hydrolysis
of PIP2 in a dose-dependent manner. WEB 2086 (100 μM) blocked inositol-1,4,5-trisphosphate formation down to baseline levels (IC50=33±12 μM WEB 2086). In thrombin and ADP stimulated platelets, inositol phosphate (IP) generation was not influenced by WEB
2086. It is concluded that WEB 2086 selectively antagonizes PAF-induced increases in IP and does not interfere directly with
intracellular signal transduction. Instead, WEB 2086, which has been shown to bind specifically and with high affinity (Ki 15 nM) to human platelets, acts as a competitive antagonist at the PAF receptor level.
Based on a paper presented at the Third International Confrence on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
4.
Jorge Casals-Stenzel 《Lipids》1991,26(12):1157-1161
The platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, (PAF) antagonistic activity of thienotriazolodiazepines has recently been described. The lead compound
in this series was brotizolam, which also exhibits sedative and hypnotic effects. By combination of brotizolam with the benzodiazepine
receptor antagonist RO 15-1788, PAF antagonistic and central nervous system (CNS) activities could be segregated. Systematic
structure variation has led to potent and selective PAF antagonists without CNS effects. WEB 2086 and its analogues WEB 2170
and STY 2108 are representative examples of this structural type and have shown a high potency and selectivity in PAF-induced
and PAF-dependentin vitro tests and in experimental models. Studies in healthy volunteers have demonstrated potent pharmacological activity and good
safety and tolerance of oral, intravenous or inhaled WEB 2086 in man. These agents should therefore prove useful for the further
elucidation of the pathophysiological role of PAF and provide an opportunity for therapeutic applications in diseases in which
the involvement of PAF has been implicated.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
5.
Hubert O. Heuer 《Lipids》1991,26(12):1369-1373
Pharmacological data obtained with hetrazepinoic platelet-activating factor (PAF) antagonists, such as apafant (WEB 2086)
and bepafant (WEB 2170), indicate a role for PAF in septic shock and in the priming process. The effect of PAF antagonists
in different models of shock states favors a role for PAF in endotoxin associated lethality, activation of inflammatory blood
cells with release of mediators, cardiovascular failure and increased vascular permeability, and in the development of shock
organs and organ failure. The priming process (e.g., by endotoxin or tumor necrosis factor) towards an increased susceptibility towards minute amounts of PAF has to be taken
into account when considering the pathophysiological significance of PAF underin vivo conditions and in septic shock.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
6.
The bacterial chemotactic peptide, formyl-methionyl-leucyl-phenylalanine (fMLP), induces the generation of platelet-activating
factor (PAF), the mobilization of arachidonic acid and generation of superoxide anion (O2
−) in rabbit polymorphonuclear leukocytes (PMNs). The PAF receptor antagonists, WEB 2086 (10–100 μM) and CV 6209 (1–10 μM),
reduced the mobilization of arachidonic acid and the O2
− generation in response to fMLP but not that in response to A23187. Pretreatment of PMNs with the phospholipase A2 inhibitor, chloroquine, or the serine protease inhibitor, tosyl-phenylalanine chloromethyl ketone, reduced the fMLP-stimulated
generation of PAF and also reduced the generation of O2
−. The respiratory burst induced by a submaximal concentration of phorbol myristate acetate was not affected by these compounds.
These data are consistent with the suggestion that endogenous PAF may contribute to the signal transduction cascade initiated
by fMLP.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May, 1989. 相似文献
7.
Demokritos Tsoukatos Constantinos A. Demopoulos Alexandros D. Tselepis Michael C. Moschidis Andreas Donos Angelos Evangelou Jaques Benveniste 《Lipids》1993,28(12):1119-1124
Evidence is presented that cardiolipin, a naturally occurring phospholipid, inhibits the aggregatory effect of platelet-activating
factor (paf) on rabbit plateletsin vitro. Bovine heart cardiolipin was shown to inhibit the aggregation of washed rabbit platelets induced by 1×10−10 M and 2×10−10 M paf with IC50 values (doses for half-maximal inhibition) of 8.4±0.8×10−7 M and 2.6±0.6×10−6 M, respectively. Phosphonocardiolipin was also able to inhibit platelet aggregation induced by 1× 10−10 M paf with an IC50 value of 3±1×10−7M. Both compounds, in concentrations up to 1×10−5 M, were unable to aggregate washed rabbit platelets and failed to inhibit the aggregation induced by 0.9 and 1.8 μM adenosine
diphosphate or 0.2–1.0 μM arrchidonic acid. By contrast, the acetylated derivative of cardiolipin exerted an aggregatory effect
on aspirin-treated rabbit platelets in the presence of creatine phosphate/creatine phosphokinase. This aggregation was inhibited
by the specific paf antagonists BN 52021 and WEB 2086. Also, platelets treated with acetyl-cardiolipin were insensitive to
the aggregatory effect of paf. Phosphatidic acid, phosphatidylglycerol,bis(dipalmitoylglycero)phosphate and their phosphono analogues were totally inactive. Similar data were obtained when platelet-rich
plasma was used instead of washed rabbit platelets. Our results support the hypothesis that the effect of cardiolipin is mediated
through specific paf receptors that act on the rabbit platelet membrane. 相似文献
8.
Compounds biologically similar to platelet activating factor are present in stored blood components 总被引:2,自引:0,他引:2
Christopher C. Silliman Chris A. Johnson Keith L. Clay Gail W. Thurman Daniel R. Ambruso 《Lipids》1993,28(5):415-418
Agents which prime the neutrophil NADPH oxidase develop during routine storae of whole blood and packed red blood cells. This
plasma priming activity can be inhibited by bepafant (WEB 2170), a specific platelet activating factor (PAF) receptor antagonist.
Quantitation of the priming agent(s), by a commercially available radioimmunoassay for PAF, reproducibly demonstrated high
levels of PAF activity. However, analysis of these plasma samples from stored blood components by gas chromatography/mass
spectroscopy did not reveal any 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. We conclude that the polyclonal antibody to PAF used in these studies may have recognized different
epitopes of a family of heterogeneous, biologically active lipids that manifest their effects through the PFA receptor. 相似文献
9.
Hubert O. Heuer Harald Darius Helmut F. Lohmann Juergen Meyer Manuela Schierenberg Norbert Treese 《Lipids》1991,26(12):1381-1385
The purpose of the present study was to determine whether increased levels of platelet-activating factor (PAF) type activity
can be detected in plasma from patients with septicemia and other diseases. A level of PAF below 0.5 ng/mL of plasma was considered
normal. We found that plasma from a patient with adverse anaphylactoidic reaction to intravenous analgetics contained 2.1
ng PAF/mL. In seven patients with septicemia, including urosepsis, endocarditis and peritonitis, and with positive blood culture,
increased plasma PAF levels (1–20 ng PAF/mL) were observed. Other patients with clinical indications of septicemia had negative
blood cultures and/or increased levels of C-reactive protein (CRP). Yet, in the plasma from these patients, no increased PAF
levels were detected under the assay conditions used. Two patients with allergic asthma, requiring treatment with steroids,
had no measurable plasma PAF. In the plasma from a patient with idiopathic thrombocytopenic purpura (ITP) only an “endogenous”
inhibitor of PAF induced platelet aggregation was initially observed. In spite of this, the patient responded to treatment
with the PAF antagonist WEB 2086 with a dramatic increase in platelet count (Lohmannet al., Lancet ii, 1147, 1988). Thereafter, also increased PAF levels (3.3 ng PAF/mL) were detected in plasma, although some “endogenous” inhibitor
of PAF was still present. In conclusion, increased PAF levels in plasma from patients support a role of PAF in certain human
disease states, such as in anaphylactoid reaction, sepsis and septic shock. The type, relevance and specificity of endogenous
inhibitors of PAF deserve further study.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
10.
Renal vascular escape is a physiological phenomenon of adaptation that occurs in vascular smooth muscle. It has been described
in many preparations subjected to electrical stimulation or treated with vasoactive agents, such as noreprinephrine, angiotensin
and vasopressin. We have recently demonstrated that a naturally occurring ginkgolide (BN 52021), which is a PAF antagonist,
was able to block norepinephrine-induced escape in perfused rabbit kidney. In the present work other PAF antagonists, such
as the ginkgolides BN 52022 and BN 52024, and the synthetic compounds 48740 RP and WEB 2086, were tested. Their effects on
renal vascular escape, perfusion pressure and tachyphylaxis were evaluated. They all were shown to block the escape. Among
the ginkgolides, BN 52024 is generally recognized as one of the weaker PAF antagonists. However, in spite of this, BN 52024
was able to significantly and simultaneously block renal vascular escape and tachyphylaxis in perfused rabbit kidney infused
with norepinephrine.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
11.
Addition of platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) to leukocyte-rich plasma from several species resulted in the rapid and pronounced activation of
the PAF biosynthetic enzyme acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase (EC 2.3.1.67). Activation of acetyltransferase by PAF occurred in leukocyte-rich
plasma from human, chimpanzee, rhesus monkey, and dog. The neutrophil was indicated to be the major cellular source of the
activabable acetyltransferase in leukocyte-rich plasma. The induction of acetyltransferase was substantial with 10 nM PAF,
and maximal at 10–30 seconds. Measurable acetyltransferase activation was significantly greater when the PAF-activated cells
were separated from the plasma by centrifugation before the acetyltransferase assay. This may be due in part to the removal
of the PAF-specific acetylhydrolase present in plasma which can cleave the acetyl group from PAF. Measuring PAF activation
of acetyltransferase in leukocyte-rich plasma can be useful to determine the potency of PAF antagonists with neutrophils in
plasma compared to isolated neutrophils in aqueous buffer, and as anex vivo assay to determine the efficacy and plasma concentration equivalents of antagonists administered to whole animals. The PAF
antagonist L-659,989 was shown to be 3–5 times more potent in inhibiting PAF induction of acetyltransferase in isolated human
neutrophils than in human leukocyte-rich plasma, with IC50 values of 10 nM and 40 nM, respectively. In theex vivo assay, oral administration of the PAF antagonist L-667, 131 to dogs resulted in very substantial inhibition of PAF induction
of acetyltransferase in the leukocyte-rich plasma. Utilizing theex vivo assay, oral administration of 1 mg/kg L-659,989 to rats was found to result in plasma concentration equivalents of approximately
200–300 nM L-659,989. Our findings offer a new approach for charagerizing thein vitro andin vivo efficacy of PAF receptor antagonists and demonstrate that PAF may be able to activate neutrophils in the bloodin vivo, further enhancing PAF synthesis.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
12.
The metabolism of 1-acyl-2-acetyl-sn-glycero-3-phosphocholine (1-acyl-PAF), a naturally occurring analogue of platelet activating factor (PAF), was investigated
in rabbit platelets. Our studies showed that 1-acyl-[3H]PAF (1-palmitoyl-2-acetyl-sn-glycero-3-phospho[N-methyl-3H]-choline) was converted by platelets into phosphatidyl-[3H]choline ([3H]PC) in a time-dependent fashion. The formation of [3H]PC occurred at a rate similar to that observed when lyso-[3H]PC (palmitoyl-sn-glycero-3-phospho[N-methyl-3H]choline) was used as substrate. In addition, a time-dependent increase in the level of water-soluble radioactivity was observed
during the incubation of platelets with either 1-acyl-[3H]PAF or lyso-[3H]PC. This increase was parallel to the formation of [3H]PC and was not observed in the presence of [14C]PAF (1-octadecyl-2-acetyl-sn-glycerol-3-phospho[N methyl-14C]choline). Analysis by thin-layer chromatography showed that the soluble radioactivity was mainly associated with glycerophosphocholine
(GPC). On the other hand, the preincubation of platelets with phenylmethylsulfonyl fluoride, an inhibitor of the acetylhydrolase,
reduced the hydrolysis of 1-acyl-[3H]PAF to [3H]GPC with a concomitant accumulation of radioactivity in 1-acyl-PAF. These findings suggest that 1-acyl-PAF is converted
into PC through deacetylation-reacylation with lysoPC as an obligatory intermediate. The findings also indicate that the lysoPC
resulting from 1-acyl-PAF is either reacylated to phosphatidylcholine (PC) or hydrolyzed to GPC by lysophospholipase. Finally,
we showed that the stimulation of platelets with PAF led to a time- and concentration-dependent increase in the conversion
of 1-acyl-[3H]PAF to [3H]PC. The stimulatory effect of PAF was not observed when platelets were lysed before incubation, suggesting that PAF enhances
the metabolism of 1-acyl-PAF, probably by accelerating its translocation through the plasma membrane. 相似文献
13.
There is a significant interest in the interrelationship between long-chain n-3, and n-6 fatty acids due to their ability
to modulate eicosanoid production. In general, the intake of arachidonic acid (AA) results in enhanced eicosanoid production,
whereas n-3 polyunsaturated fatty acids (PUFA) decrease the production of eicosanoids from AA. The purpose of this study was
to investigate whether the effects of dietary AA on eicosanoid production in the rat were correlated with the AA and EPA levels
in platelets and aorta (eicosanoid-producing tissues). Four groups of male Sprague-Dawley rats were fed a highfat diet enriched
with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (approximately 100 mg/day of EPA+DHA) for 24 d. During the
last 10 d, the four groups were orally supplemented with 0,30,60, and 90 mg/day of ethyl arachidonate. A further group of
rats was fed a control diet (without longchain n-3 PUFA) for 24 d.In vitro aorta prostacyclin (PGI2) production, serum thromboxane A2 (TxA2) production and plasma, and platelet and aorta phospholipid (PL) fatty acids were measured. Enriching the diet with n-3 PUFA
resulted in significant reductions in tissue AA levels and an increase in the n-3 PUFA, particularly EPA. On this diet, the
AA to EPA ratio was 1:1 in platelet PL, and it was 2:1 in the aorta PL. There were significant decreases in thein vitro PGI2 and TxA2 production compared with the control animals. The inclusion of AA in the diet resulted in marked increases in AA levels in
the platelet and aorta PL with corresponding decreases in EPA. The lowest dose of AA (30 mg/rat) reversed the effects of 100
mg/day of n-3 PUFA on AA levels in platelet and aortic PL and onin vitro aorta PGI2 and serum TxA2 production. The dietary AA caused a differential (twofold) increase in TxA2 relative to PGI2 for all three levels of AA supplementation. There were greater changes in the levels of AA and/or EPA in platelet PL compared
with the aorta PL, which might have accounted for the differential effects of these PUFA on thromboxane production compared
with PGI2 production in this study. 相似文献
14.
Toshimitsu Yamada Munetoshi Saito Toshiyasu Mase Hiromu Hara Hitoshi Nagaoka Kiyoshi Murase Kenichi Tomioka 《Lipids》1991,26(12):1179-1183
The antagonistic effect of YM461 [1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine fumarate] against
platelet-activating factor (PAF) was examined in severalin vitro andin vivo systems. We found that YM461 inhibited [3H]PAF binding to rabbit platelet membranes with a pKi value of 8.90. YM461 inhibited PAF induced rabbit and human platelet aggregation with pA2 values of 7.52 and 7.29, respectively; the slopes of the Schild plots were 1.07 and 1.01, respectively. However, YM461 at
10−4M did not affect rabbit and human platelet aggregation induced by ADP, collagen, arachidonic acid or epinephrine. YM461 inhibited
PAF induced death in mice with an ED50 (50% effective dose) value of 0.35 mg/kgp.o. YM461 at doses above 0.3 mg/kgi.v. inhibited PAF induced hypotension in rats. YM461 showed a dose-dependent inhibition of PAF induced hemoconcentration in rats
with ED50 values of 0.15 and 0.21 mg/kgp.o., respectively, at 0.5 and 1 hr after oral administration. The anti-PAF effect of YM461 persisted more than 6 hr after 3 mg/kgp.o. in rats. YM461 inhibited the bronchoconstriction induced by PAF with an ED50 value of 1.2 mg/kgp.o. in anesthetized guinea pigs. Furthermore, the compound at doses above 3 mg/kgp.o. significantly inhibited antigen-induced anaphylactic asthma in conscious guinea pigs pretreated with mepyramine and propranolol.
These results indicate that YM461 is a selective, potent and orally active PAF antagonist.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献
15.
Norihiko Shimazaki Ichiro Shima Masanori Okamoto Keizo Yoshida Keiji Hemmi Masashi Hashimoto 《Lipids》1991,26(12):1175-1178
FR900452, a natural product isolated from the culture broth ofStreptomyces phaeofaciens No. 7739, was found to inhibit PAF-induced rabbit platelet aggregation with an IC50 of 3.7×10−7M. FR900452, 1-methyl-3-[1-[5-methylthiomethyl-6-oxo-3-(2-oxo-3-cyclopenten-1-ylidene)-2-piperazinyl]ethyl]-2-indoline, has
an oxocylopentylidene group incorporated as a vinylogous amide in a diketopiperazine skeleton. This unique structure led us
to synthesize diketopiperazine derivatives, 3-arylalkyl-6-substituted-piperazine-2,5-diones. their observed PAF inhibitory
activity suggest that the D-D configuration of diketopiperazine is an important factor for anti-PAF activity and that the
hydrophobic aromatic portion may play a specific role in the binding of the diketopiperazine to the PAF receptor.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Ether
Lipids Tokyo, Japan, May 1989. 相似文献
16.
William J. Houlihan Mark L. Lee Paul G. Munder Georgina M. Nemecek Dean A. Handley Christine M. Winslow John Happy Christian Jaeggi 《Lipids》1987,22(11):884-890
SRI 62-834, an analog of the antitumor agent ET-18-OCH3 in which the oxygen atom at carbon atom 2 has been incorporated into a five-membered heterocycle, has been prepared and evaluated as an antitumor agent. The compound exhibited good cytotoxicity in vitro against a variety of tumor cell lines and was as effective as ET-18-OCH3 given orally in the mouse Meth A sarcoma model. SRI 62-834 was shown to be an inhibitor of platelet-derived growth factor (PDGF), possibly at the receptor level, and platelet-activating factor (PAF) at the receptor level. 相似文献
17.
Yuliy Y. Chirkov Thanh H. Nguyen John D. Horowitz 《International journal of molecular sciences》2022,23(3)
The propensity towards platelet-rich thrombus formation increases substantially during normal ageing, and this trend is mediated by decreases in platelet responsiveness to the anti-aggregatory nitric oxide (NO) and prostacyclin (PGI2) pathways. The impairment of soluble guanylate cyclase and adenylate cyclase-based signalling that is associated with oxidative stress represents the major mechanism of this loss of anti-aggregatory reactivity. Platelet desensitization to these autacoids represents an adverse prognostic marker in patients with ischemic heart disease and may contribute to increased thrombo-embolic risk in patients with heart failure. Patients with platelet resistance to PGI2 also are unresponsive to ADP receptor antagonist therapy. Apart from ischemia, diabetes and aortic valve disease are also associated with impaired anti-aggregatory homeostasis. This review examines the association of impaired platelet cyclic nucleotide (i.e., cGMP and cAMP) signalling with the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses the potential therapeutic strategies targeting this abnormality. 相似文献
18.
The individual molecular species composition of diacyl, alkylacyl and alkenylacyl glycerophospholipids was determined in mouse
peritoneal macrophages. A marked deterogeneity in the relative composition (mol%) of macrophage ether and ester phospholipid
individual species was noted. High concentrations of 16∶0–20∶4 were found in ether phospholipids such as alkenylacyl glycerophosphoethanolamine
(GPE; 27.5 mol%) and alkylacyl glycerophosphocholine (GPC; 16.6%) as compared to mol % levels of 16∶0–20∶4 in diacyl GPE (5.7%)
and diacyl GPC (8.1%), respectively. Interestingly, alkenylacyl GPE was highly enriched in 1-ether (16∶0) relative to alkylacyl
GPC. The predominant diacyl molecular species in glycerophosphoinositol (GPI) and glycerophosphoserine (GPS) were 18∶0–20∶4
(59.1%) and 16∶0–18∶1 (41.1%), respectively. It is noteworthy that the level of 18∶0–20∶4 was several times higher in diacyl
GPI (59.1%) than in diacyl GPS (11.1%), diacyl GPE (25.7%), and diacyl GPC (3.7%). The most abundant molecular species in
diacyl GPC and diacyl GPE were 16∶0–18∶1 (29.9%) and 18∶0–20∶4 (25.7%), respectively. The abundance of 20∶4 in ether phospholipids,
specifically 16∶0–20∶4 and 18∶0–20∶4, in alkylacyl GPC is significant in view of the role these antecedents play in the biosynthesis
of platelet-activating factor (PAF) and 20∶4-derived eicosanoids in stimulated macrophages. The unique molecular species composition
of the peritoneal macrophage distinguishes this cell type from others. 相似文献
19.
Jen-sie Tou 《Lipids》1989,24(9):812-817
This study extended the earlier finding that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) promotes arachidonic acid incorporation into neutrophil phosphatidylinositol (PI) and phosphatidylcholine
(PC). In the present study the effect of PAF on fatty acid uptake by human neutrophils and the incorporation of extracellular
linoleic acid and palmitic acid into phospholipids were investigated. Incubation of 10−7 M PAF with neutrophils and radiolabeled arachidonic acid or linoleic acid or palmitic acid for 1–10 min resulted in an increased
rate of loss of label from the incubation medium. PAF stimulated the incorporation of linoleic acid and palmitic acid most
significantly into PI and PC. The magnitude of stimulation was greater in PI than in PC for the incorporation of linoleic
acid, and vice versa for the incorporation of palmitic acid. The positional distribution of linoleic acid and palmitic acid
in PI and PC and the mass of these phospholipids were not altered in PAF-stimulated neutrophils. An increased incorporation
of all three fatty acids into both diacyl and alkylacyl species of PC was demonstrated after a two minute incubation of cells
with PAF. While more radioactivity was recovered in the diacyl species, the magnitude of increase of radioactivity in the
alkylacyl species was more pronounced than that in the diacyl species of PC. These results suggest that both increased fatty
acid uptake and increased available lysophospholipids may be contributory to the increased phospholipid acylation induced
by PAF. 相似文献
20.
H. O. Heuer 《Lipids》1991,26(12):1374-1380
The selective hetrazepinoic platelet-activating factor (PAF) antagonist WEB 2170 (Bepafant) was used to study the pathophysiological
role of PAF in several models of anaphylaxis in mice and guinea pigs. In actively sensitized mice, the PAF antagonist WEB
2170 (1.0–10 mg/kgp.o.) protected mice from anaphylactic death in a dosedependent manner when the anaphylactic response was potentiated by the beta-receptor
antagonist propranolol. When active anaphylaxis in guinea pigs was induced intravenously by 100 mg/kg ovalbumin (OA) in the
presence of small doses of the antihistamine mepyramine, additional treatment with oral or intravenous WEB 2170 protected
the guinea pigs from anaphylactic death. Also, the remaining anaphylactic bronchoconstriction and blood pressure changes (including
anaphylactic hypotension) were attenuated. When guinea pigs were passively sensitized with a heterologous antibodyvia the tracheal route and then challenged by ovalbumin (100 mg/kgi.v.) 24 hr after sensitization in the presence of 0.003 mg/kgi.v. mepyramine, additional treatment with tracheal WEB 2170 at 0.1–1 mg/kg protected the guinea pigs dosedependently not only
from anaphylactic death but also from a further decrease of respiratory flow and changes of blood pressure. Increased levels
of PAF-like activity (20–50 ng PAF/whole lung) were detected in lungs removed from antigen-challenged animals. The results
suggest a causative role for PAF in active and passive anaphylaxis.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, Tokyo, Japan, May 1989. 相似文献